This invention relates to novel thienopyridine and thienopyridine derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Compounds that are useful in the treatment of hyperproliferative diseases are also disclosed in the following patents and applications: PCT international patent application publication number WO 00/38665 (published Jul. 6, 2001), PCT international patent application publication number WO 97/49688 (published Dec. 31, 1997), PCT international patent application publication number WO 98/23613 (published Jun. 4, 1998), U.S. patent application Ser. No. 60/299,879 (filed Jun. 21, 2001), U.S. patent application Ser. No. 09/502,129 (filed Feb. 10, 2000), U.S. patent application No. 60/209,686 (filed Jun. 6, 2000), U.S. patent application No. 60/214,373 (filed Jun. 28, 2000), U.S. patent application Ser. No. 08/953,078 (filed Oct. 17, 1997), U.S. Pat. No. 6,071,935 issued Jun. 6, 2000, PCT international patent application publication number WO 96/30347 (published Oct. 3, 1996), PCT international patent application publication number WO 96/40142 (published Dec. 19, 1996), PCT international patent application publication number WO 97/13771 (published Apr. 17, 1997), and PCT international patent application publication number WO 95/23141 (published Aug. 31, 1995). The foregoing patent and applications are incorporated herein by reference in their entirety.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e., a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are large enzymes that span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate a specific tyrosine residue in proteins and hence to influence cell proliferation. The foregoing tyrosine kinases may be classified as growth factor receptor (e.g. EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. It is known that such kinases are often aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. Aberrant erbB2 activity has been implicated in breast, ovarian, non-small cell lung, pancreatic, gastric and colon cancers. It has also been shown that epidermal growth factor receptor (EGFR) is mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Thus, it is believed that inhibitors of receptor tyrosine kinases, such as the compounds of the present invention, are useful as selective inhibitors of the growth of mammalian cancer cells.
It has also been shown that EGFR inhibitors may be useful in the treatment of pancreatitis and kidney disease (such as proliferative glomerulonephritis and diabetes-induced renal disease), and may reduce successful blastocyte implantation and therefore may be useful as a contraceptive. See PCT international application publication number WO 95/19970 (published Jul. 27, 1995), hereby incorporated by reference in its entirety.
It is known that polypeptide growth factors such as vascular endothelial growth factor (VEGF) having a high affinity to the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor have been associated with the proliferation of endothelial cells and more particularly vasculogenesis and angiogenesis. See PCT international application publication number WO 95/21613 (published Aug. 17, 1995), hereby incorporated by reference in its entirety. Agents, such as the compounds of the present invention, that are capable of binding to or modulating the KDR/FLK-1 receptor may be used to treat disorders related to vasculogenesis or angiogenesis such as diabetes, diabetic retinopathy, age related macular degeneration, hemangioma, glioma, melanoma, Kaposi""s sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
A compound represented by the formula I 
wherein
X is xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94;
Y is xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH2xe2x80x94;
R1 is H, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94C(O)(C1-C6 alkyl), C6-C10 aryl or a 5 to 13 membered heterocyclic, wherein said C6-C10 aryl and 5 to 13 membered heterocyclic groups are unsubstituted or substituted with 1 to 5 R5 substituents;
each R5 is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, xe2x80x94C(O)R8, xe2x80x94C(O)OR8, xe2x80x94OC(O)R8, xe2x80x94OC(O)OR8, xe2x80x94NR6C(O)R7, xe2x80x94C(O)NR6R7, xe2x80x94NR6R7, xe2x80x94OR9, xe2x80x94SO2NR6R7, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C6 alkylamino, xe2x80x94(CH2)jO(CH2)qNR6R7, xe2x80x94(CH2)tO(CH2)9OR9, xe2x80x94(CH2)tOR9, xe2x80x94S(O)j(C1-C6 alkyl), xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94C(O)(CH2)t(C6-C10 aryl), xe2x80x94(CH2)tO(CH2)j(C6-C10 aryl), xe2x80x94(CH2)tO(CH2)q(5 to 10 membered heterocyclic), xe2x80x94C(O)(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)jNR7(CH2)qNR6R7, xe2x80x94(CH2)jNR7CH2C(O)NR6R7, xe2x80x94(CH2)jNR7(CH2)qNR9C(O)R8, (CH2)jNR7(CH2)tO(CH2)qOR9, xe2x80x94(CH2)jNR7(CH2)qS(O)j(C1-C6 alkyl), xe2x80x94(CH2)jNR7(CH2)tR6, xe2x80x94SO2(CH2)t(C6-C10 aryl), and xe2x80x94SO2(CH2)t(5 to 10 membered heterocyclic), wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the xe2x80x94(CH2)qxe2x80x94 and xe2x80x94(CH2)txe2x80x94 moieties of the said R5 groups optionally include a carbon-carbon double or triple bond where t is an integer between 2 and 6, and the alkyl, aryl and heterocyclic moieties of the said R5 groups are unsubstituted or substituted with one or more substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, xe2x80x94OH, xe2x80x94C(O)R8, xe2x80x94C(O)OR8, xe2x80x94OC(O)R8, xe2x80x94OC(O)OR8, xe2x80x94NR6C(O)R7, xe2x80x94C(O)NR6R7, xe2x80x94(CH2)tNR6R7, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tO(CH2)qOR9, and xe2x80x94(CH2)tOR9, wherein t is an integer from 0 to 6 and q is an integer from 2 to 6;
each R6 and R7 is independently selected from H, OH, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tO(CH2)qOR9, xe2x80x94(CH2)tCN(CH2)tOR9, xe2x80x94(CH2)tCN(CH2)tR9 and xe2x80x94(CH2)tOR9, wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the said R6 and R7 groups are unsubstituted or substituted with one or more substituents independently selected from hydroxy, halo, cyano, nitro, trifluoromethyl, azido, xe2x80x94C(O)R8, xe2x80x94C(O)OR8, xe2x80x94CO(O)R8, xe2x80x94OC(O)OR8, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, C1-C6 alkyl, xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tO(CH2)qOR9, and xe2x80x94(CH2)tOR9, wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, where when R6 and R7 are both attached to the same nitrogen, then R6 and R7 are not both bonded to the nitrogen directly through an oxygen;
each R8 is independently selected from H, C1-C10 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)t(C6-C10 aryl), and xe2x80x94(CH2)t(5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R9 and R10 is independently selected from H, xe2x80x94OR6, C1-C6 alkyl, and C3-C10 cycloalkyl; and,
R11 is H, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94C(O)NR12R13, xe2x80x94C(O)(C6-C10 aryl), xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tNR12R13, xe2x80x94SO2NR12R13 and xe2x80x94CO2R12, wherein t is an integer from 0 to 6, wherein said C1-C6 alkyl, xe2x80x94C(O)(C6-C10 aryl), xe2x80x94(CH2)t(C6-C10 aryl), and xe2x80x94(CH2)t(5 to 10 membered heterocyclic) moieties of the said R11 groups are unsubstituted or substituted by one or more R5 groups;
each R12 and R13 is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)t(C3-C10 cycloalkyl), xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tO(CH2)qOR9, and xe2x80x94(CH2)tOR9, q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the said R12 and R13 groups are unsubstituted or substituted with one or more substituents independently selected from R5, or R12 and R13 are taken together with the nitrogen to which they are attached to form a C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, wherein said C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl rings are unsubstituted or substituted with one or more R5 substituents, where R12 and R13 are not both bonded to the nitrogen directly through an oxygen;
or prodrugs thereof, or pharmaceutically acceptable salts or solvates of said compounds and said prodrugs.
In another embodiment of the compound of formula I R11 is xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94C(O)NR12R13, xe2x80x94SO2NR12R13 and xe2x80x94CO2R12, wherein t is an integer from 0 to 6, wherein said R11 group xe2x80x94(CH2)t(5 to 10 membered heterocyclic) is unsubstituted or substituted by one or more R5 groups and wherein each R12 and R13 is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)t(C3-C10 cycloalkyl), xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tO(CH2)qOR9, xe2x80x94(CH2)tOR9, q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of said R12 and R13 groups are unsubstituted or substituted by one or more substituents independently selected from R5, or R12 and R13 are taken together with the nitrogen to which they are attached to form a C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, wherein said C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring are unsubstituted or substituted by one or more R5 substituents, where said R12 and R13 are not both bonded to the nitrogen directly through an oxygen.
In another embodiment of the compound of formula I R11 is xe2x80x94(CH2)t(5 to 10 membered heterocyclic), and xe2x80x94C(O)NR12R13, wherein t is an integer from 0 to 6, wherein said R11 group xe2x80x94(CH2)t(5 to 10 membered heterocyclic) is unsubstituted or substituted with one or more R5 groups and wherein each R12 and R13 is independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)t(C3-C10 cycloalkyl), xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tO(CH2)qOR9, xe2x80x94(CH2)tOR9, q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of said R12 and R13 groups are unsubstituted or substituted by one or more substituents independently selected from R5, or R12 and R13 are taken together with the nitrogen to which they are attached to form a C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, wherein said C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring are unsubstituted or substituted with one or more R5 substituents, where R12 and R13 are not both bonded to the nitrogen directly through an oxygen.
In still another embodiment of the compound of formula I R11 is xe2x80x94C(O)NR12R13, wherein R12 and R13 are independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)t(C3-C10 cycloalkyl), xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tO(CH2)qOR9, xe2x80x94(CH2)tOR9, wherein t is an integer from 0 to 6, q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of said R12 and R13 groups are unsubstituted or substituted with one or more substituents independently selected from R5, or R12 and R13 are taken together with the nitrogen to which they are attached to form a C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, wherein said C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring are unsubstituted or substituted with 1 to 5 R5 substituents, where R12 and R13 are not both bonded to the nitrogen directly through an oxygen.
In another embodiment of the compound of formula I R11 is xe2x80x94C(O)NR12R13, wherein R12 and R13 are taken together with the nitrogen to which they are attached to form a C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, wherein said C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring are unsubstituted or substituted with 1 to 5 R5 substituents.
In still another preferred embodiment of the compound of formula I R11 is xe2x80x94C(O)NR12R13, wherein R12 and R13 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, wherein said pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring are unsubstituted or substituted with 1 to 5 R5 substituents.
In still another preferred embodiment of the compound of formula I R11 is xe2x80x94C(O)NR12R13, wherein R12 and R13 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl ring, wherein said pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl rings are unsubstituted or substituted with 1 to 5 R5 substituents.
In another preferred embodiment of the compound of formula I R11 is xe2x80x94C(O)NR12R13, wherein R12 and R13 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl or piperidinyl ring, wherein said pyrrolidinyl or piperidinyl ring are unsubstituted or substituted with 1 to 5 R5 substituents.
In another preferred embodiment of the compound of formula I R11 is xe2x80x94C(O)NR12R13, wherein R12 and R13 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl ring, wherein said pyrrolidinyl is unsubstituted or substituted with 1 to 5 R5 substituents.
In another preferred embodiment of the compound of formula I R11 is xe2x80x94C(O)NR12R13, wherein R12 and R13 are taken together with the nitrogen to which they are attached to form a pyrrolidin-1-yl ring, wherein said pyrrolidin-1-yl is unsubstituted or substituted by 1 to 5 R5 substituents.
In another preferred embodiment of the compound of formula I R11 is xe2x80x94(CH2)t(5 to 10 membered heterocyclic) group, wherein t is an integer from 0 to 6, said xe2x80x94(CH2)t(5 to 10 membered heterocyclic) group is unsubstituted or substituted by 1 to 5 R5 groups.
In another preferred embodiment of the compound of formula I R11 is xe2x80x94(CH2)t(5-8 membered heterocyclic) group, wherein t is an integer from 0 to 6, said xe2x80x94(CH2)t(5-8 membered heterocyclic) group is unsubstituted or substituted by 1 to 5 R5 groups.
In another preferred embodiment of the compound of formula I R11 is xe2x80x94(CH2)t(5 or 6 membered heterocyclic) group, wherein t is an integer from 0 to 6, said xe2x80x94(CH2)t(5 or 6 membered heterocyclic) group is unsubstituted or substituted by 1 to 5 R5 groups.
In another preferred embodiment of the compound of formula I R11 is xe2x80x94(CH2)t(5 membered heterocyclic) group, wherein t is an integer from 0 to 6, said xe2x80x94(CH2)t(5 membered heterocyclic) group is unsubstituted or substituted by 1 to 5 R5 groups.
In another preferred embodiment the compound of formula I R11 is xe2x80x94(CH2)tthiazolyl, wherein t is an integer from 0 to 6, said xe2x80x94(CH2)tthiazolyl is unsubstituted or substituted by 1 to 5 R5 groups.
In another preferred embodiment, the compound of formula I, R11 is a thiazolyl, said thiazolyl is unsubstituted or substituted by 1 to 5 R5 groups.
In another preferred embodiment, the compound of formula I, R11 is an imidazolyl, said imidazolyl is unsubstituted or substituted by 1 to 5 R5 groups.
Other preferred compounds include those of formula I wherein R1 is phenyl unsubstituted or substituted with 1 to 5 R5 substituents, or R1 is a group of the formula 
wherein X2 is xe2x80x94Sxe2x80x94 or xe2x80x94N(R6)xe2x80x94, X3 is N or CH, the dashed line in formula 3 represents an optional double bond, and the above R1 groups of formulas 3 and 5 are unsubstituted or substituted with 1 to 5 R5 substituents and the R1 groups of formulas 4 and 6 are unsubstituted or substituted with 1 to 3 R5 substituents. Specifically preferred compounds include those wherein R1 is a group of formula 3 above wherein said group is unsubstituted or substituted by 1 to 5 R5 substituents.
The present invention also relates to intermediate compounds of the formula II 
and to pharmaceutically acceptable salts thereof, wherein:
Z1 is halo, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CSNH2 and Z2 is xe2x80x94OR1; or Z1 is R11 and Z2 is halo; or
Z1 and Z2 are each independently halo; X is N or CH; and wherein R1 and R11 are as defined for said compounds of formula I. The above intermediates of formula III may be used to prepare the above compounds of formula I.
A compound represented by the formula III 
wherein:
Y is xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94;
R14 is C1-C6 alkyl, C1-C6 alkylamino, C3-C10 cycloalkylamino, or methylureido;
R15, R16 and R17 are independently H, halo, or C1-C6 alkyl group; and
R11 is a heteroaryl group unsubstituted or substituted by one or more halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, xe2x80x94C(O)R8, xe2x80x94C(O)OR8, xe2x80x94OC(O)R8, xe2x80x94OC(O)OR8, xe2x80x94NR6C(O)R7, xe2x80x94C(O)NR6R7, xe2x80x94NR6R7, xe2x80x94OR9, xe2x80x94SO2NR6R7, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)jO(CH2)qNR6R7, xe2x80x94(CH2)tO(CH2)qOR9, xe2x80x94(CH2)tOR9, xe2x80x94S(O)j(C1-C6 alkyl), xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94C(O)(CH2)t(C6-C10 aryl), xe2x80x94(CH2)tO(CH2)j(C6-C10 aryl), xe2x80x94(CH2)tO(CH2)q(5 to 10 membered heterocyclic), xe2x80x94C(O)(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)jNR7(CH2)qNR6R7, xe2x80x94(CH2)jNR7CH2C(O)NR6R7, xe2x80x94(CH2)jNR7(CH2)qNR9C(O)R8, (CH2)jNR7(CH2)tO(CH2)qOR9, xe2x80x94(CH2)jNR7(CH2)qS(O)j(C1-C6 alkyl), xe2x80x94(CH2)jNR7 xe2x80x94(CH2)tR6, xe2x80x94SO2(CH2)t(C6-C10 aryl), and xe2x80x94SO2(CH2)t(5 to 10 membered heterocyclic), wherein j is an integer from 0 to 2, t is an integer from 0 to 6, q is an integer from 2 to 6, the xe2x80x94(CH2)qxe2x80x94 and xe2x80x94(CH2)txe2x80x94 moieties of the said R5 groups optionally include a carbon-carbon double or triple bond where t is an integer between 2 and 6, and the alkyl, aryl and heterocyclic moieties of the said R5 groups are unsubstituted or substituted with one or more substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, xe2x80x94OH, xe2x80x94C(O)R8, xe2x80x94C(O)OR8, xe2x80x94OC(O)R8, xe2x80x94OC(O)OR8, xe2x80x94NR6C(O)R7, xe2x80x94C(O)NR6R7, xe2x80x94(CH2)tNR6R7, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tO(CH2)qOR9, and xe2x80x94(CH2)tOR9, wherein t is an integer from 0 to 6 and q is an integer from 2 to 6;
R6 and R7 is independently selected from H, OH, C1-C6 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tO(CH2)qOR9, and xe2x80x94(CH2)tOR9, wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the said R6 and R7 groups are unsubstituted or substituted with one or more substituents independently selected from hydroxy, halo, cyano, nitro, trifluoromethyl, azido, xe2x80x94C(O)R8, xe2x80x94C(O)OR8, xe2x80x94CO(O)R8, xe2x80x94OC(O)OR8, xe2x80x94NR9C(O)R10, xe2x80x94C(O)NR9R10, xe2x80x94NR9R10, C1-C6 alkyl, xe2x80x94(CH2)t(C6-C10 aryl), xe2x80x94(CH2)t(5 to 10 membered heterocyclic), xe2x80x94(CH2)tO(CH2)qOR9, and xe2x80x94(CH2)tOR9, wherein t is an integer from 0 to 6 and q is an integer from 2 to 6, where when R6 and R7 are both attached to the same nitrogen, then R6 and R7 are not both bonded to the nitrogen directly through an oxygen;
each R8 is independently selected from H, C1-C10 alkyl, C3-C10 cycloalkyl, xe2x80x94(CH2)t(C6-C10 aryl), and xe2x80x94(CH2)t(5 to 10 membered heterocyclic), wherein t is an integer from 0 to 6;
each R9 and R10 is independently selected from H, C1-C6 alkyl, and C3-C10 cycloalkyl; or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs.
Specific embodiments of the present invention include the following compounds: 
or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs.
This invention also relates to pharmaceutical compositions containing and methods for treating abnormal cell growth through administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
The invention also relates to a pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically effective amount of a compound of formula I, or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs, and a pharmaceutically acceptable carrier. In one embodiment, said pharmaceutical composition is for the treatment of cancer such as brain, lung, ophthalmic, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesophageal, gynecological or thyroid cancer. In another embodiment, said pharmaceutical composition is for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., benign prostatic hypertropy (BPH)).
The invention also relates to a pharmaceutical composition for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-induced renal disease) in a mammal which comprises a therapeutically effective amount of a compound of formula I, or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs, and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for the prevention of blastocyte implantation in a mammal which comprises a therapeutically effective amount of a compound of formula I, or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs, and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which comprises a therapeutically effective amount of a compound of formula I, or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs, and a pharmaceutically acceptable carrier. In one embodiment, said pharmaceutical composition is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi""s sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
The invention also relates to a method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of the compound of formula I, or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs. In one embodiment, said method relates to the treatment of cancer such as brain, ophthalmic, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, lung, renal, kidney, ovarian, gynecological or thyroid cancer. In another embodiment, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., benign prostatic hypertropy (BPH)).
The invention also relates to a method for the treatment of a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula I, or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
The invention also relates to a method of treating pancreatitis or kidney disease in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula I, or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs.
The invention also relates to a method of preventing blastocyte implantation in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula I, or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs.
The invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal which comprises administering to said mammal an effective amount of a compound of formula I, or prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs. In one embodiment, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi""s sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
Patients that can be treated with the compounds of formula I, and prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds and said prodrugs, according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis, BPH, lung cancer, eye cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin""s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphonas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms of the central nervous system (e.g., primary CNS lymphona, spinal axis tumors, brain stem gliomas or pituitary adenomas).
This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the formula I as defined above, or prodrug thereof, pharmaceutically acceptable salt or solvate of said compound and said prodrug, that is effective in inhibiting farnesyl protein transferase, and a pharmaceutically acceptable carrier.
This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of formula I, or prodrug thereof, pharmaceutically acceptable salt or solvate of said compound and said prodrug, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, salt, solvate, or prodrug, and of the chemotherapeutic are together effective in inhibiting abnormal cell growth. Many chemotherapeutics are presently known in the art. In one embodiment, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, e.g. anti-androgens.
This invention further relates to a method for inhibiting abnormal cell growth in a mammal which method comprises administering to the mammal an amount of a compound of formula I, or prodrug thereof, pharmaceutically acceptable salt or solvate of said compound and said prodrug, in combination with radiation therapy, wherein the amount of the compound, salt, solvate or prodrug is in combination with the radiation therapy effective in inhibiting abnormal cell growth in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein.
It is believed that the compounds of formula I can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of formula I or prodrug thereof, pharmaceutically acceptable salt or solvate of said compound and said prodrug, which amount is effective in sensitizing abnormal cells to treatment with radiation. The amount of the compound, salt, solvate or prodrug in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
This invention also relates to a method of and to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of formula I, or prodrug thereof, pharmaceutically acceptable salt or solvate of said compound and said prodrug, or an isotopically-labelled derivative thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of formula 1 and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX(trademark) (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European Patent Application No. 97304971.1 (filed Jul. 8, 1997), European Patent Application No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European Patent Publication 606,046 (published Jul. 13, 1994), European Patent Publication 931,788 (published Jul. 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filed Jul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar. 25, 1999), Great Britain patent application number 9912961.1 (filed Jun. 3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent Publication 780,386 (published Jun. 25, 1997), all of which are incorporated herein in their entireties by reference. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
Some specific examples of MMP inhibitors useful in the present invention are Prinomastat, RO 32-3555, RS 13-0830, and the compounds recited in the following list: 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic acid; 3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; (2R,3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic acid; 4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide; (R) 3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid hydroxyamide; (2R,3R) 1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionic acid; 3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionic acid; 3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; 3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; and (R) 3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide; and pharmaceutically acceptable salts and solvates of said compounds.
Other anti-angiogenesis agents, including other COX-II inhibitors and other MMP inhibitors, can also be used in the present invention.
A compound of formula I, can also be used with signal transduction inhibitors, such as agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors, such as VEGF receptors and molecules that can inhibit VEGF; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTIN(trademark) (Genentech, Inc. of South San Francisco, Calif., USA).
EGFR inhibitors are described in, for example in WO 95/19970 (published Jul. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO 98/02434 (published Jan. 22, 1998), and U.S. Pat. No. 5,747,498 (issued May 5, 1998), and such substances can be used in the present invention as described herein. EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, N.Y., USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, N.J., USA), and OLX-103 (Merck and Co. of Whitehouse Station, N.J., USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Mass.). These and other EGFR-inhibiting agents can be used in the present invention.
VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA), can also be combined with the compound of the present invention. VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17, 1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat. No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), WO 99/10349 (published Mar. 4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596 (published Jun. 26, 1997), WO 98/54093 (published Dec. 3, 1998), WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO 98/02437 (published Jan. 22, 1998), all of which are incorporated herein in their entireties by reference. Other examples of some specific VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Wash., USA); anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, Calif.; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.). These and other VEGF inhibitors can be used in the present invention as described herein.
ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), can furthermore be combined with the compound of the invention, for example those indicated in WO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (published Jan. 22,1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2, 1999), which are all hereby incorporated herein in their entireties by reference. ErbB2 receptor inhibitors useful in the present invention are also described in U.S. Provisional Application No. 60/117,341, filed Jan. 27, 1999, and in U.S. Provisional Application No. 60/117,346, filed Jan. 27, 1999, both of which are incorporated in their entireties herein by reference. The erbB2 receptor inhibitor compounds and substance described in the aforementioned PCT applications, U.S. patents, and U.S. provisional applications, as well as other compounds and substances that inhibit the erbB2 receptor, can be used with the compounds of the present invention.
The compounds of the invention can also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, and the like. Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Provisional Application 60/113,647 (filed Dec. 23, 1998) which is incorporated by reference in its entirety, however other CTLA4 antibodies can be used in the present invention.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula I, II, or III of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
The compounds of formula I and their pharmaceutically acceptable salts and solvates can each independently also furthermore be used in a palliative neo-adjuvant/adjuvant therapy in alleviating the symptoms associated with the diseases recited herein as well as the symptoms associated with abnormal cell growth. Such therapy can be a monotherapy or can be in a combination with chemotherapy and/or immunotherapy.
The terms xe2x80x9ccomprisingxe2x80x9d and xe2x80x9cincludingxe2x80x9d are used herein in their open, non-limiting sense.
The terms xe2x80x9cabnormal cell growthxe2x80x9d and xe2x80x9chyperproliferative disorderxe2x80x9d are used interchangeably in this application.
xe2x80x9cAbnormal cell growthxe2x80x9d, as used herein, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), including the abnormal growth of normal cells and the growth of abnormal cells. This includes, but is not limited to, the abnormal growth of: (1) tumor cells (tumors), both benign and malignant, expressing an activated Ras oncogene; (2) tumor cells, both benign and malignant, in which the Ras protein is activated as a result of oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs. Examples of such benign proliferative diseases are psoriasis, benign prostatic hypertrophy, human papilloma virus (HPV), and restinosis. xe2x80x9cAbnormal cell growthxe2x80x9d also refers to and includes the abnormal growth of cells, both benign and malignant, resulting from activity of the enzyme farnesyl protein transferase.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, means saturated monovalent hydrocarbon radicals having straight, cyclic or branched moieties. Said xe2x80x9calkylxe2x80x9d group may include an optional carbon-carbon double or triple bond where said alkyl group comprises at least two carbon atoms. It is understood that for cyclic moieties at least three carbon atoms are required in said alkyl group.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, means O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is as defined above.
The term xe2x80x9cheteroalkylxe2x80x9d as used herein refers to straight- and branched-chain alkyl groups having from one to twelve atoms containing one or more heteroatoms selected from S, O, and N.
The term xe2x80x9calkenylxe2x80x9d refers to straight- and branched-chain alkenyl groups having from two to twelve carbon atoms. Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like.
The term xe2x80x9calkynylxe2x80x9d refers to straight- and branched-chain alkynyl groups having from two to twelve carbon atoms. Illustrative alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a monocyclic or polycyclic radical which may be saturated or unsaturated and contains carbocycles having from three to twelve carbon atoms, including bicyclic and tricyclic cycloalkyl structures.
A xe2x80x9cheterocycloalkylxe2x80x9d group refers to a monocyclic or polycyclic radical which may be saturated or unsaturated and contains from three to twelve ring atoms, selected from carbon and heteroatoms, preferably 4 or 5 ring carbon atoms, and at least one heteroatom selected from nitrogen, oxygen and sulfur.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, means an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The terms xe2x80x9c5 membered heterocyclicxe2x80x9d, xe2x80x9c5 or 6 membered heterocyclicxe2x80x9d, xe2x80x9c5 to 8 membered heterocyclicxe2x80x9d, xe2x80x9c5 to 10 membered heterocyclicxe2x80x9d or xe2x80x9c5 to 13 membered heterocyclicxe2x80x9d, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 5, 6, 5 to 8, 5 to 10 or 5 to 13 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo (xe2x95x90O) moieties such as pyrrolidin-2-one. An example of a 5 membered heterocyclic group is thiazolyl, an example of a 10 membered heterocyclic group is quinolinyl, and an example of a 13 membered heterocyclic group is a carbazole group. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazoyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl and thiazolyl. Heterocyclic groups having a fused benzene ring include benzimidazolyl, benzofuranyl, and benzo[1,3]dioxolyl. The term xe2x80x9calcoholxe2x80x9d refers to the radical xe2x80x94Rxe2x80x94OH where R is alkyl, alkenyl, alkynyl, Ar, heteroaryl, heterocycloalkyl, or cycloalkyl as defined above. Examples of alcohols include methanol, ethanol, propanol, phenol and the like.
The term xe2x80x9cacylxe2x80x9d represents xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94OC(O)R or xe2x80x94OC(O)OR where R is alkyl, alkenyl, alkynyl, Ar, heteroaryl, heterocycloalkyl, or cycloalkyl as defined as above.
The term xe2x80x9camidexe2x80x9d refers to the radical xe2x80x94C(O)N(Rxe2x80x2)(Rxe2x80x3) where Rxe2x80x2 and Rxe2x80x3 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, xe2x80x94OH, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl, aryl as defined above; or Rxe2x80x2 and Rxe2x80x3 cyclize together with the nitrogen to form a heterocycloalkyl or heteroaryl as defined above.
The term xe2x80x9calcoholxe2x80x9d refers to the radical xe2x80x94Rxe2x80x94OH where R is alkyl, alkenyl, alkynyl, Ar, heteroaryl, heterocycloalkyl, or cycloalkyl as defined above. Examples of alcohols include methanol, ethanol, propanol, phenol and the like.
The term xe2x80x9cacylxe2x80x9d represents xe2x80x94C(O)R, xe2x80x94C(O)OR, xe2x80x94OC(O)R or xe2x80x94OC(O)OR where R is alkyl, alkenyl, alkynyl, Ar, heteroaryl, heterocycloalkyl, or cycloalkyl as defined as above.
The term xe2x80x9camidexe2x80x9d refers to the radical xe2x80x94C(O)N(Rxe2x80x2)(Rxe2x80x3) where Rxe2x80x2 and Rxe2x80x3 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, xe2x80x94OH, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl, aryl as defined above; or Rxe2x80x2 and Rxe2x80x3 cyclize together with the nitrogen to form a heterocycloalkyl or heteroaryl as defined above.
The term xe2x80x9csubstitutedxe2x80x9d as used herein means that the group in question, e.g., alkyl group, etc., may bear one or more substituents.
The alkyl, cycloalkyl, aryl, heterocyclyl groups and the substituents containing these groups, as defined hereinabove, may be optionally substituted by at least one other substituent. The term xe2x80x9coptionally substitutedxe2x80x9d is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more substituents from the list above. Various groups may be unsubstituted or substituted (i.e., they are optionally substituted) as indicated.
If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley and Sons, NY (1999), which is incorporated herein by reference in its entirety. In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound.
The compounds of the present invention may have asymmetric carbon atoms. Such diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomer mixtures and pure enantiomers are considered as part of the invention.
The compounds of present invention may in certain instances exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The term xe2x80x9cprodrugxe2x80x9d, as used herein, unless otherwise indicated, means compounds that are drug precursors, which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of formula I. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
It will be appreciated that any solvate (e.g. hydrate) form of compounds of formula I and prodrugs thereof can be used for the purpose of the present invention.
xe2x80x9cA pharmaceutically acceptable saltxe2x80x9d is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, xcex3-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Pharmaceutical compositions according to the invention may, alternatively or in addition to a compound of Formula I, comprise as an active ingredient pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds and metabolites. Such compounds, prodrugs, multimers, salts, and metabolites are sometimes referred to herein collectively as xe2x80x9cactive agentsxe2x80x9d or xe2x80x9cagents.xe2x80x9d
In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.
Therapeutically effective amounts of the active agents of the invention may be used to treat diseases mediated by modulation or regulation of protein kinases. An xe2x80x9ceffective amountxe2x80x9d is intended to mean that amount of an agent that significantly inhibits proliferation and/or prevents de-differentiation of a eukaryotic cell, e.g., a mammalian, insect, plant or fungal cell, and is effective for the indicated utility, e.g., specific therapeutic treatment.
The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. xe2x80x9cTreatingxe2x80x9d is intended to mean at least the mitigation of a disease condition in a subject such as mammal (e.g., human), that is affected, at least in part, by the activity of one or more kinases, for example protein kinases such as tyrosine kinases, and includes: preventing the disease condition from occurring in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but has not yet been diagnosed as having it; modulating and/or inhibiting the disease condition; and/or alleviating the disease condition.
Agents that potently regulate, modulate, or inhibit cell proliferation are preferred. For certain mechanisms, inhibition of the protein kinase activity associated with CDK complexes, among others, and those which inhibit angiogenesis and/or inflammation are preferred. The present invention is further directed to methods of modulating or inhibiting protein kinase activity, for example in mammalian tissue, by administering an inventive agent. The activity of agents as anti-proliferatives is easily measured by known methods, for example by using whole cell cultures in an MTT assay. The activity of the inventive agents as modulators of protein kinase activity, such as the activity of kinases, may be measured by any of the methods available to those skilled in the art, including in vivo and/or in vitro assays. Examples of suitable assays for activity measurements include those described in International Publication No. WO 99/21845; Parast et al., Biochemistry, 37, 16788-16801 (1998); Connell-Crowley and Harpes, Cell Cycle: Materials and Methods, (Michele Pagano, ed. Springer, Berlin, Germany)(1995); International Publication No. WO 97/34876; and International Publication No. WO 96/14843. These properties may be assessed, for example, by using one or more of the biological testing procedures set out in the examples below.
The active agents of the invention may be formulated into pharmaceutical compositions as described below. Pharmaceutical compositions of this invention comprise an effective modulating, regulating, or inhibiting amount of a compound of Formula I or Formula II and an inert, pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical compositions, efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving anti-proliferative ability. By xe2x80x9cefficacious levelsxe2x80x9d is meant levels in which proliferation is inhibited, or controlled. These compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.
An inventive agent can be administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
A variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of an inventive agent can be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or combinations of cosolvents. Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
It will be appreciated that the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease being treated. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for an agent. For oral administration, an exemplary daily dose generally employed is from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals. Administration of prodrugs is typically dosed at weight levels that are chemically equivalent to the weight levels of the fully active form.
The compositions of the invention may be manufactured in manners generally known for preparing pharmaceutical compositions, e.g., using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks""s solution, Ringer""s solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of agents.
Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the agents in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions take the form of tablets or lozenges formulated in conventional manners.
For administration intranasally or by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the agents in water-soluble form. Additionally, suspensions of the agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
For administration to the eye, the agent is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary, lens, choroid/retina and sciera. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material. A compound of the invention may also be injected directly into the vitreous and aqueous humor.
Alternatively, the agents may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g, containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described above, the agents may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
An exemplary pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5 W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
The agents of the invention may be useful in combination with known anti-cancer treatments such as: DNA interactive agents such as cisplatin or doxorubicin; topoisomerase II inhibitors such as etoposide; topoisomerase I inhibitors such as CPT-II or topotecan; tubulin interacting agents such as paclitaxel, docetaxel or the epothilones; hormonal agents such as tamoxifen; thymidilate synthase inhibitors such as 5-fluorouracil; and anti-metalbolites such as methotrexate. They may be administered together or sequentially, and when administered sequentially, the agents may be administered either prior to or after administration of the known anticancer or cytotoxic agent.
The agents may be prepared using the reaction routes and synthesis schemes as described below, employing the general techniques known in the art using starting materials that are readily available. The preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other anti-proliferatives or protein kinase inhibitors of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or generally known in the art will be recognized as having applicability for preparing other compounds of the invention.